Io Therapeutics is developing a novel agonist for the Retinoid X Receptors (RXR), IRX4204, to treat multiple sclerosis (MS) and other autoimmune diseases. RXR is a key nuclear receptor involved in inflammation. It has a role in regulating immunity through the enhancement of Treg activities and suppression of inflammatory Th17 activities. Because of the importance of RXR in controlling immunity, small molecule agonists and antagonists for these nuclear receptors have become attractive drug candidates. Io developed IRX4204 as a second-generation RXR specific agonist that belongs to the rexinoid class of compounds. It binds with very high affinity and selectivity to the RXRs, IRX 4204 has very limited affinity for the Retinoic Acid Receptors (RAR). In functional transactivation assays, IRX4204 is at least 2,000 fold more potent in activating RXR homodimers than RAR-RXR heterodimers and IRX4204 does not activate other heterodimers such as RXR-PPAR, RXR-LXR, and RXR-FXR. This selectivity confers increased safety of IRX4204 because it will not produce toxicities found with agonists of RAR. In fact, IRX4204 has undergone extensive preclinical development as an anticancer drug. IND-enabling studies included 30-day GLP toxicology studies in rats and dogs, GLP safety studies of effects of the compound on the cardiovascular, respiratory, and CNS, and the full standard panel of GLP gene toxicity studies. Io was granted an IND by FDA for clinical testing of IRX4204 in human safety studies and in 44 patients with various cancers, in phase I and phase II clinical trials, has been found safe and well tolerated for up to 20 months of treatment. This indicates that if IRX4204 is found effective in animal models of MS then it can be rapidly transitioned into testing for safety and efficacy in MS patients, especially since Io Therapeutics has an active IND for clinical testing. Preliminary data show that IRX4204 is effective in preclinical MS efficacy studies. In collaboration with Drs. Randolph Noelle and Elizabeth Nowak at Dartmouth Medical School, IRX4204 was found effective in reducing experimental autoimmune encephalomyelitis (EAE), an animal model of MS. It reduced disease severity and CNS infiltration of CD4 T cells in an EAE model in B6 mice and was similarly effective in an EAE model in SJL mice. Studies proposed in this grant will confirm and extend these studies testing efficacy of IRX4204 in three different MS animal models to identify optimal dosing needed in designing future clinical testing of the drug in MS patients. We will further define the mechanism of action of IRX4204 to provide insights into potential markers to use to determine efficacy of the drug in humans. In this regard, our finding that IRX4204 is a potent activator of the RXR-Nurr1 heterodimer is of interest since Nurr1 has been reported to induce Foxp3 expression and Treg-like activity in native CD4 T cells We propose that IRX4204 is a unique immunoregulatory drug, resetting Treg and Th17 function to restore immune homeostasis that will be efficacious in treating MS and other immune disorders. Our goal is to develop IRX4204 as a safe and effective treatment of MS.